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Bruce H. Littman, Frank W Marcoux, Jeffrey Adam Jamison; Efficacy of PPL-003 and the Role of NFκB Activation in a Rat Model of Dry Eye Disease. Invest. Ophthalmol. Vis. Sci. 2016;57(12):407.
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© ARVO (1962-2015); The Authors (2016-present)
NFκB signaling following innate immune system-mediated activation has been implicated in the pathogenesis of dry eye disease. PPL-003 is a cell penetrating peptide (CPP) that includes a human-derived CPP sequence and a region able to reduce NFkB activation by blocking formation of the upstream IkB kinase complex. The efficacy of topical PPL-003 in rats with established dry eye-induced corneal pathology was evaluated.
Male Sprague Dawley rats received Alzet Pump implantation (2ML4) on Day 0 for continuous scopolamine administration (2.5 µL/hr). Rats were then kept in a low humidity chamber for 28 days with treatments beginning on Day 14. Groups of 5 rats each received topical administration to both eyes of 5mL t.i.d. of one of three concentrations of PPL-003 (1.66 mg/ml, 0.45 mg/ml or 0.03 mg/ml), vehicle or 0.1% dexamethasone. To rule out a vehicle effect a sixth group received no treatment. Corneal staining was scored according to The National Eye Institute’s standardized grading system.
Reduced corneal staining was noted in all PPL-003 treatment groups compared to vehicle while scores for vehicle and no treatment groups were similar (Figure 1.). Efficacy was best determined by comparing scores on Day 21 with scores at the start of treatment on Day 14 since after day 21 spontaneous improvement was noted in the vehicle and no treatment groups due to reduced scopolamine delivery. P-values comparing scores at the start of treatment on day 14 to scores on days 17, 21 and 28 and between treatments on day 21 are given in Table 1. PPL-003 scores on day 21 were significantly lower than day 14 scores at all doses and were quantitatively superior to dexamethasone.
PPL-003 efficacy confirmed the importance of NFκB activation in this dry eye disease model. This finding supports further development of topical PPL-003 for dry eye disease and NFκB activation as a therapeutic target with potentially broader steroid-like effects compared to agents that target only a specific pro-inflammatory mediator such as adhesion molecules, chemotactic factors and cytokines.
This is an abstract that was submitted for the 2016 ARVO Annual Meeting, held in Seattle, Wash., May 1-5, 2016.
Figure 1: Mean Corneal Scores
Table 1: Corneal Score P-values (2-tail T-test)
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